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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mpv17l protects against mitochondrial oxidative stress and apoptosis by activation of Omi/HtrA2 protease
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Mpv17l protects against mitochondrial oxidative stress and apoptosis by activation of Omi/HtrA2 protease

机译：Mpv17l通过激活Omi / HtrA2蛋白酶来保护线粒体氧化应激和细胞凋亡

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摘要

Cellular localization determines whether the serine protease HtrA2 exerts pro- or antiapoptotic functions. In contrast to the well-characterized proapoptotic function of cytosolic HtrA2, mechanisms underlying the mitochondrial protective role are poorly understood. Mpv17l is a transmembrane protein previously implicated in peroxisomal reactive oxygen species metabolism and a close homolog of the inner mitochondrial membrane protein Mpv17. Here we demonstrate a previously undescribed direct interaction between Mpv17l and HtrA2 in mitochondria. The interaction is mediated by a PDZ domain and induces protease activation of HtrA2. HtrA2 inhibits mitochondrial superoxide generation, stabilizes mitochondrial membrane potential, and prevents apoptosis at baseline and in response to extracellular induc-ers of mitochondrial stress. The physiological role of Mpv17l is underscored by the finding that oxidative stress-induced down-regulation of Mpv17l is a consistent feature in renal injury models. Our findings identify Mpv17l as a unique interacting protein and regulator of HtrA2 protease mediating antioxidant and antiapoptotic function in mitochondria.
机译：细胞定位确定丝氨酸蛋白酶HtrA2是否发挥促凋亡或抗凋亡功能。与良好表征的细胞溶质HtrA2的促凋亡功能相反，对线粒体保护作用的潜在机制了解甚少。 Mpv17l是一种跨膜蛋白，以前与过氧化物酶体的活性氧代谢有关，与内部线粒体膜蛋白Mpv17密切相关。在这里，我们证明了线粒体中Mpv17l和HtrA2之间以前未描述的直接相互作用。该相互作用由PDZ结构域介导，并诱导HtrA2的蛋白酶活化。 HtrA2抑制线粒体超氧化物的产生，稳定线粒体膜电位，并防止基线时以及对线粒体应激的细胞外诱导物的反应引起的细胞凋亡。通过发现氧化应激诱导的Mpv17l的下调在肾脏损伤模型中是一致的特征，来强调Mpv17l的生理作用。我们的发现确定Mpv17l是介导线粒体中抗氧化剂和抗凋亡功能的HtrA2蛋白酶的独特相互作用蛋白和调节剂。

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